tbuckley/cabot-search huggingface dataset:
Phase II study of trifluridine/tipiracil (FTD/TPI) in HER2-negative metastatic breast cancers with or without prior exposure to fluoropyrimidines.
Authors: Joline Si Jing Lim, Samuel Guan Wei Ow, Andrea Wong, Matilda Lee, Gloria HJ Chan, Jia Li Low, Raghav Sundar, Joan RE Choo, Bee Choo Tai, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2023)

1099 Background: Fluoropyrimidines are commonly used in the treatment of patients (pts) with metastatic breast cancers (MBC). FTD/TPI is an oral drug combination of trifluridine with tipiracil, a thymidine phosphorylase inhibitor preventing rapid degradation of trifluridine, thus allowing for increased exposure to active agent, and has showed activity in pts with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in MBC pts with (Cohort A) or without (Cohort B) prior exposure to fluoropyridines in a single arm phase II study. Methods: Pts were treated with FTD/TPI, and enrolled first into a lead-in dose confirmation phase, followed by two parallel cohorts based on prior exposure to fluoropyrimidines. Primary objectives for each cohort included determination of progression-free survivals (PFS), and secondary objectives included determination of objective response rates (ORR), safety and tolerability. Results: A total of 74 pts were recruited (42 for Cohort A, 32 for Cohort B), of whom 4 belonged to lead-in phase. Dosing was confirmed at FTD/TPI 35mg/m 2 days 1-5 and 8-12 of 4-weekly cycles based on lead-in phase with no dose-limiting toxicities observed, and recruitment then proceeded in 2 parallel cohorts. All pts were evaluable for toxicity and survival analyses, and 72 were evaluable for ORR. Median age at enrolment was 62 years (range 32-85), with median of 4 (range 0-14) prior lines therapy in the metastatic setting, and 47% had de novo metastatic disease. Median PFS was 5.7 months (95% CI 3.8 to 8.3) and 9.4 months (95% CI 5.5 to 14.0) respectively in Cohorts A and B. Similar response rates were observed regardless of prior exposure to fluoropyrimidine, with ORR of 19.5% (95% CI 8.8 to 34.9) and 16.1% (95% CI 5.5 to 33.7) in Cohorts A and B, with 6-month clinical benefit rates of 56.1% (95% CI 39.7 to 71.5) and 61.3% (95% CI 42.2 to 78.2) respectively. Safety profile was consistent with known toxicities of FTD/TPI, with most common treatment-related adverse events of neutropenia, fatigue, nausea and anorexia. 64% of pts required dose modifications during study treatment, most commonly due to neutropenia, that could be overcome by dose reduction or prolongation from 4- to 5-weekly cycles. Only 1 pt required discontinuation due to toxicity from therapy. Conclusions: FTD/TPI showed promising anti-tumor activity with meaningful clinical benefit even among pts with prior exposure to fluoropyrimidines, and has a reasonable toxicity profile with appropriate dose modification. An oral chemotherapy option with good disease control provides an attractive treatment alternative to pts with MBC where quality of life is paramount, warranting further investigation in randomised studies. Clinical trial information: NCT04280536 .
Moderate physical exercise and immune system modulation in patients with breast cancer treated with neoadjuvant chemotherapy.
Authors: Ornella Garrone, Matteo Paccagnella, Andrea Abbona, Fiorella Ruatta, Paola Vanella, Gianluca Tomasello, Nicoletta Croce, Francesca Barbin, Maria Grazia Rossino, Marco Carlo Merlano
Journal: Journal of Clinical Oncology (2023)

605 Background: The link between physical activity (PA) and immune system is known. However, are not clearly understood which mechanisms are activated by PA. We investigated the effect of moderate PA (MPA), on a panel of circulating cytokines during neoadjuvant chemotherapy (CT) in patients (pts) with breast cancer. Methods: Pts received sequential epirubicin and cyclophosphamide for 4 cycles followed by weekly paclitaxel ± trastuzumab. MPA consisted of Nordic or fit walking, 3 workouts/week, 1 hour each, in the 9 weeks before Surgery (S). Blood samples were collected in pts underwent MPA (TR) and in a group of pts who declined MPA (UN) at baseline (T0), at day 1 of week 6 of paclitaxel (starting MPA) (T1) and before S (T2). At each time point the level of 22 cytokines (IL1b, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12, IL13, IL15, IL17a, IL18, IL21, CCL2, CCL4, CXCL10, CCL22, IFNγ, TGFβ, TNFα, VEGF) was measured using Simple Plex Ella. Sample size was calculated using effect size method considering a Cohen’s d of 0.65 as observed for a candidate cytokine (IL-6) between two groups. Considering a desired statistical power of 0.8 and a probability level of 0.05 a minimum of 78 patients were required. The difference among the median value of cytokines was analysed using non parametric Mann Whitney U test. Comparisons between time points in the same group were analysed with Wilcoxon signed-rank test. Results: Accrual is completed. 61 pts were TR and 20 UN. Main patients’ characteristics are listed. At T0 IL4, IL17, IL18 and VEGF level was significantly higher in UN respect to TR pts. At T1 IL4, IL17 and IL18 level remained significantly higher in UN pts. At T2, UN pts showed significantly higher value of IL4, IL6, IL7, IL8, IL17, IL18 VEGF and TGFβ. IL21 was significantly higher in TR pts. Longitudinal analysis between T0 and T1 in TR and UN pts showed significantly lower level of CCL22 and significantly higher level of IL7, IL13 and CXCL10 in TR pts and significantly higher level of IL8 in UN pts. Longitudinal analysis between T1 and T2 showed significantly higher level of IL21, CXCL10, CCL22, TNFα and significantly lower level of IFNγ, IL6, IL8, CCL2, TGFβ in TR pts and significantly lower level of CXCL10 in UN pts. Conclusions: TR and UN pts differed modestly at baseline including acceptance of MPA. The longitudinal analysis T0-T1 showed that CT induced more evident changes in TR than in UN pts. Longitudinal analysis T1-T2 demonstrated major changes in Th1 and Th2 cytokines only in TR pts. Overall, CT induced weak changes in UN and greater changes in TR pts strengthened by the addition of MPA. These observations suggest a more efficient immune system in TR pts and a possible additional benefit derived from MPA. [Table: see text]
Image-only deep learning risk model performance in patients with known germline mutations.
Authors: Faezeh Sodagari, Constance Dobbins Lehman, Sarah Mercaldo, Andrew Carney, Leslie Lamb
Journal: Journal of Clinical Oncology (2023)

536 Background: Mammograms contain highly predictive biomarkers of future breast cancer risk, which can be identified by deep learning (DL) risk stratification models. DL model performance in discerning risk in patients with known germline mutations has yet to be established. The aim of this study is to assess image-only DL model risk score performance in patients with and without a germline mutation undergoing screening breast MRI. Methods: This retrospective, multisite study included the first screening MRI of consecutive females ≥30 years from 3/1/2011 to 11/30/2021 at four facilities, with a prior bilateral screening mammogram containing a DL risk score and at least one year of follow-up. A mammography-based DL five-year model was used to assess risk, with an increased-risk threshold of ≥2.2 and high-risk of ≥5.8. Patient demographics, germline mutation status, and traditional risk factors were extracted from electronic medical records. Standard screening performance metrics including cancer detection rate (CDR) within one year of MRI were determined. Cancer outcomes were determined via linkage to a regional tumor registry. DL model performance was compared using Pearson’s chi-squared tests. Results: 4025 patients who underwent screening breast MRI met inclusion criteria. 381(9.5%) had a known germline mutation. There was no significant difference in age of those with or without a germline mutation (54.9y ± 10.5 vs 54.8y ± 8.8, p = 0.284) or family history of breast cancer (68.5% vs 65.3%, p = 0.205). Patients with a germline mutation were more likely to be White (95.0 vs 91.4%, p &lt; 0.05), have non-dense breasts (52.8% vs 35.3%, p &lt; 0.001) and less likely to have a personal history of breast cancer (25.7% vs 36.3%, p &lt; 0.001). The CDR in those with a germline mutation was higher than those without a mutation (39.4 vs 20.3, p &lt; 0.05). The median DL risk score in those with a germline mutation was lower than those without a mutation: 1.9 (IQR: 1.4-2.5) vs 2.3 (IQR: 1.7-3.8), p &lt; 0.001. In patients with a germline mutation, the CDR in those with elevated DL scores was higher than those with low DL scores (47.6 vs 34.2, p = 0.512: increased-risk threshold; 60.6 vs 37.4, p = 0.512: high-risk threshold). A similar trend was seen in those without a germline mutation (26.4 vs 12.8, p &lt; 0.01: increased-risk threshold; 27.1 vs 19.0, p = 0.203: high-risk threshold). Trends were demonstrated across all comparisons, but significance was only reached in the largest group. Conclusions: Compared to patients without germline mutations, those with mutations had higher CDRs on MRI but lower DL risk scores. Patients with higher DL risk scores had higher CDRs in those identified as increased or high-risk by DL model, regardless of germline mutation status. Further study to elucidate mechanisms to explain differential performance of DL models in patients with germline mutations is ongoing.
Characterizing the mental health of South African women living with comorbid HIV and breast cancer.
Authors: Daniel O'Neil, Charmaine Blanchard, Maureen Joffe, Molly Ream, Gugulethu Tshabalala, Alain Diaz, Wenlong Carl Chen, Nontlantla Mkwanazi, Bonnie Blomberg, Michael Antoni
Journal: Journal of Clinical Oncology (2023)

e12549 Background: In South Africa’s public hospitals, 20% of new breast cancer (BC) diagnoses are in women living with HIV (WLWH). These women experience 49% higher mortality than BC patients without HIV. Mental health disorders are prevalent in both WLWH and women with BC. Symptoms of depression, anxiety, and acute stress are linked to increased circulating serum inflammatory markers, which may provide a pathophysiologic explanation for poorer outcomes. We aimed to explore whether South African BC patients living with HIV report more mental health symptoms than women with HIV alone, BC alone, or neither and to determine if comorbid HIV and BC is associated with greater systemic inflammation. Methods: We conducted a cross-sectional study of black South African women ≥18 years old. We enrolled four arms: newly diagnosed BC patients with HIV, newly diagnosed BC patients without HIV, WLWH without BC, and women with benign breast diagnoses. Participants were recruited from the breast clinic or HIV clinic at Chris Hani Baragwanath Academic Hospital. Consenting women completed the Center for Epidemiologic Studies Depression Scale (CES-D), the Generalized Anxiety Disorder 7-item Scale (GAD-7), and the Perceived Stress Scale (PSS). Blood samples were tested for serum concentrations of inflammatory markers (c-reactive protein (CRP) and S100A8/A9), pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α), and anti-inflammatory cytokines (IL-4, IL-5, and IL-10) via ELISA assays performed at the University of Miami. Results: The first three arms enrolled 25 women each and the benign arm enrolled 22 women. Participant scores on the CES-D, GAD-7, and PSS were higher than expected in all groups and seemed to be worse in participants with HIV alone. Scores consistent with clinical depression, moderate to severe anxiety, and moderate to severe stress were reported by 68-88%, 28-76%, and 72-94% of participants, respectively. We found trends towards higher concentrations of CRP, TNF-α, IL-6, and IL-8 in participants with co-morbid BC and HIV versus benign breast disease but no pattern of increased inflammatory marker concentrations in participants with dual diagnoses versus either diagnosis alone. Conclusions: Our pilot study did not find evidence of increased mental health symptom burden or systemic inflammation in South African women with comorbid breast cancer and HIV, versus either diagnosis alone. Increased mental health symptoms in women with HIV alone may reflect reduced access to supportive service available at the HIV clinic compared to the breast clinic. [Table: see text]
The worldwide impact of HER2-targeted treatments in women with breast cancer: An epidemiological modeling study.
Authors: David J. Press, Melina Arnold, Svenn Hansen
Journal: Journal of Clinical Oncology (2023)

543 Background: HER2-targeted therapies (trastuzumab, pertuzumab, and T-DM1) have revolutionized the treatment and epidemiological landscape of HER2+ breast cancer, resulting in population-level increases in survival and decreases in disease recurrence. The aim of this epidemiological modeling study was to quantify the estimated global impact of HER2-targeted therapies, by estimating the number of women diagnosed with HER2+ early breast cancer (eBC) who have avoided (or will avoid) metastatic disease recurrence following treatment. Methods: We used data and projections from cancer registries, observational studies, clinical trials, and drug sales volumes (ie, utilization) to create annual country-level synthetic cohorts of patients diagnosed with HER2+ eBC, for the years 2004-2033 in 185 countries. The real-world uptake of HER2-targeted treatments and treatment flow was estimated in the main scenario. The impact of chemotherapy alone was estimated in the counterfactual scenario, assuming 100% chemotherapy worldwide. The occurrence of distant recurrences was modeled in both scenarios using weighted transitional probability averages based on invasive disease-free survival curves from clinical trials. Results: In total, during the 3-decade study period, we predicted that 11.9 million (M) women would be diagnosed with HER2+ eBC, out of which 7.5M were estimated to be treated with HER2-targeted therapies in a real-world uptake scenario. In the counterfactual scenario with only chemotherapy available, a total of 2.9M women were estimated to experience a metastatic disease recurrence, compared to only 2.1M women in the base scenario of predicted real-world uptake of HER2+ targeted therapies. This corresponds to a reduction of 26% or 768,000 women who may avoid metastatic recurrence since the introduction of HER2-targeted therapies (Table). Conclusions: HER2+ targeted therapies have substantially improved breast cancer outcomes and continue to contribute to the reduction in breast cancer recurrence rates. Further research may elucidate treatment-related reductions in costs to society as a result of population-level improvements in disease outcomes for breast cancer survivors. Given the expected rise in the burden of breast cancer globally, therapeutic advances and increased treatment utilization may further accelerate global patient benefit. [Table: see text]
Preliminary results from a first-in-human study of ESG401, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients with locally advanced/metastatic solid tumors.
Authors: Fei Ma, Fuming Qiu, Zhongsheng Tong, Jiani Wang, Yinuo Tan, Rui Bai, Qing Zhou, Xiaoyan Xing
Journal: Journal of Clinical Oncology (2023)

1100 Background: ESG401 is an innovative ADC composed of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to topoisomerase I inhibitor SN-38 via a proprietary stable-cleavable linker with DAR of 8. Methods: Patients (pts) aged ≥18 years with locally advanced/metastatic solid tumors refractory to/relapsed from standard treatment with measurable disease (RECIST v1.1) were eligible. ESG401 is administered intravenously by designated dose and regimen until unacceptable toxicity or progressive disease. The Bayesian Optimal Interval (BOIN) design was used to establish the MTD. Results: As of Feb 3, 2023, 35 pts with a median age of 53 were treated with ≥1 dose of ESG401 during escalation at doses of 2-20 mg/kg once Q3W (Regimen A), or 12-16 mg/kg D1,8,15 in a 4-week cycle (Regimen B). 80% of pts were ECOG = 1, 63% of pts were 3L+; median 4 (2-10) prior lines, 94% of pts had visceral metas (11% brain, 63% liver, 60% lung) at baseline. Only one patient treated with 20 mg/kg experienced DLT. The MTD has not reached either regimen. The most common TRAEs were leukopenia (80%), neutropenia (69%), anemia (66%), fatigue (54%), nausea (51%), and vomiting (46%). The most common ≥ Grade 3 TRAEs were leukopenia (29%) and neutropenia (31%). There was no ≥ Grade 3 thrombocytopenia, diarrhea, skin rash, or oral mucositis. No Interstitial Lung Disease (ILD) was observed. Of 33 efficacy evaluable (EE) pts, 12 partial responses (PR) were observed and 4 pts had achieved SD ≥24 wks. The first dose level found PR (16 mg/kg Q3W) and afterward were taken as therapeutically relevant doses (TRD). The ORR and DCR were 36% (4/11) and 64% (7/11) in 11 TRD pts with TNBC, while 62% (8/13) and 77% (10/13) in 13 TRD pts with HR+/HER2-BC. Two pts with brain metas both got an obvious intracranial response (one pt whose intracranial lesion was significantly reduced to too small to measure). Until the cut-off date, 11 (31%) pts remained on treatment. Three pts were treated over 12 mons and the longest on-treatment duration was 12.9 mons. One pt had consistent PR up to 10.8 mons. Conclusions: The preliminary data demonstrated that ESG401 is safe and well-tolerated with promising signals of efficacy in heavily pretreated pts. These encouraging findings warrant further clinical evaluation. Clinical trial information: NCT04892342 . [Table: see text]
Clinical subtypes and survival outcomes in invasive breast cancer with Paget’s disease: A SEER population-based study.
Authors: Soo Youn Bae, Ji Eun Lee, Woo-Chan Park, Chang Ik Yoon, Dooreh Kim, Kabsoo Shin, Youngjoo Lee
Journal: Journal of Clinical Oncology (2023)

e12564 Background: The objective of this study was to investigate the clinicopathological characteristics, especially subtypes and survival outcomes of Invasive breast cancer with Paget's disease. Methods: 4930 patients were identified using the histopathology codes from the International Classification of Disease for Oncology third edition (ICD-O-3), from 2000 to 2019 in the Surveillance, Epidemiology, and End Results (SEER) database. Excluding 787 patients whose ICD-O-3 and TNM stages did not match, there were 663 patients with '8540/3, Paget disease, mammary', 976 patients with ‘8543/3, Paget disease and intraductal carcinoma(DCIS)’ and 2540 patients with ‘8541/3, and ‘8541/3, Paget disease and infiltrating ductal carcinoma (IDC) of breast’. ER and PR status have been available since 1990, and HER2 status since 2010. Results: Among patients with IDC and Paget's disease, 24.6% were under the age of 50 and 2.7% were male, which was higher than the other two groups. Expressions of ER and PR were higher than both groups, and HER2 expression was lower. The ratio of HR-/HER2+ subtype was also lower than the other two groups at 29.6%. ER+, Paget 43.7%, DCIS with Paget 36.4%, IDC with Paget 53.6%. PR+ Paget 21.6%, DCIS with Paget 21.7%, IDC with Paget 40.1%. HER2+ Paget 69.2%, DCIS with Paget 83.1 %, IDC with Paget 58.3%. HR-/HER2+subtype, Paget 40.7%, DCIS with Paget 49.2%, IDC with Paget 29.6%. As a result of survival analysis in patients with IDC and Paget's disease, the HR-/HER2+ subtype had shown the best prognosis in Overall Survival (OS) analysis (5year OS, HR+/HER2- 70.8%, HR+/HER2+ 74.9%, HR-/HER2- 63.7%, HR-/HER2+ 80.7% P=0.010) In the BCSS analysis, the 5-year BCSS was the best at 87.0% in the HR-HER2+ subtype, but there was no statistically significant difference. Conclusions: In IDC with Paget's disease, the distribution of subtypes is different from that of DCIS with Paget's, and HER2 expression can be considered as a favor prognostic factor. It is considered necessary to study the relationship between the loss of HER2 overexpression and invasion/progression in invasive breast cancer with Paget's disease.
Efficacy and safety of neoadjuvant double anti-Her2 blockade combined with anthracycline-free chemotherapy in locally advanced breast cancer.
Authors: Maria Yeray Rodriguez Garcés, Victoria García Samblás, David Morales Pancorbo, Juan Lucas Bayo Calero
Journal: Journal of Clinical Oncology (2023)

e12612 Background: Double anti-Her2 blockade combined with chemotherapy (CT) is a standard regimen in Her2 positive locally advanced breast cancer (LABC) with a high risk of relapse. TCHP provides more anti-Her2 treatment, better pathological complete response (pCR) rates and less cardiotoxicity. However, it is not a very widespread option due to the risk of toxicity. Our group shows a manageable toxicity profile by adding G-CSF as primary prohylaxis. Methods: We describe our experience with neoadjuvant TCHP and pegfilgrastim combination between years 2017-2023. Efficacy and safety were analyzed and compared with other schemes accepted by clinical guidelines. Results: 62 patients, median age 48 years; 61.3% were premenopausal; 54.8% were stage II at diagnosis and 45.2% were stage III; 67.7% had N+; 62.9% had RH-. A total of six cycles were completed in 85.5%; 8 patients discontinued treatment due to toxicity. The most frequent adverse events were hematological (grade 3-4 in 8.1%) and digestive (grade 3-4 in 19.4%). No cardiac event was reported. 6.5% were hospitalized due to toxicity (3.2% febrile neutropenia). Dose reduction was needed in 43.5%. Clinical response occurred in 98.4% and radiological response in 87.1% (complete in 38.7%). pCR (ypT0/isN0) was obtained in 67.7% (66.7% in N+; 77.4% in RH-). Up to now, 4 patients have relapsed (3 of them had pRC) and 3 have died. After median 24.5 months of follow-up, the median relapse-free and overall survival by Kapplan-Meier have not been reached. Cox regression shows that getting rPC does not impact survival. The Odds Ratio shows a higher proportion of obtaining pRC in the RH- and N+ subgroups, but without statistically significant differences. Conclusions: Our data based on combination of TCHP and pegfilgrastim shows considerable efficacy with an acceptable toxicity profile. The main advantage is the intensification of double lock dose, without anti Her2 window period, avoiding the addition of anthracyclines and, therefore, cardiac toxicity. pRC and toxicity profile results were better than other regimen proposed in other studies. Our data shows that pRC has no impact on survival. We assume a favorable association between pRC and N+ and HR-, although not statistically significant, probably due to the small amount of patients. Based on these favorable results, we believe that the priority use of TCHP-GCSF should be considered in the neoadjuvant treatment of Her2+ LABC. [Table: see text]